The goals of these studies are: 1) to define the time course, distribution and propagation of lactic acidosis and edema that result from temporary regional ischemia; 2) to relate these pathological processes to glutamate levels and the delayed irreversible cellular injury that occurs despite restoration of blood flow; and, 3) to determine whether cell necrosis or recovery can be predicted by magnetic resonance spectroscopic imaging (MRSI) of brain lactate and NAA, and by diffusion-enhanced proton imaging (DMRI). These advanced NMR imaging and spectroscopy methods developed in our laboratories will be employed to monitor the temporal and spatial evolution of injury within 10-20 min of onset of ischemia. In our regional ischemia model temporary internal carotid and MCA occlusion in rats is produced by insertion of an intraluminal suture. Previous MR observations suggest a duration dependent infarction threshold for lactate/NAA ratios of >1.5. These will be further investigated after brief (0.5h) or prolonged (2h) ischemia and reperfusion. Cellular and vasogenic edema will be assessed by measurement of tissue impedance in vivo and H2O content, Na+ and K+ concentration, Na+ - K+ ATPase activity, and Evan's blue dye permeability in vitro for correlation with D-MRI data. Total tissue lactate will be measured in vitro from cortex and striatum for calibration of MRSI results. LCBF or lCMRG and pathology results will be correlated with MRSI. Extracellular glutamate and lactate measurements from microdialysates will also be correlated with MRSI results. Inhibition of lactic acidosis by dichloroacetate and blockade of NMDA receptors by CGS 19775 will be studied to clarify the role and interaction of these mechanisms of post-ischemic cell damage.